IL‐1β and IL‐18: inflammatory markers or mediators of hypertension?

Abstract

Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1β and pro-IL-18 into their active forms thus triggering inflammation. While IL-1β and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1β/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1β and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1β/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension.

High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

“…Our renal transcriptome data, however, supported that fiber lowered IL-1 signaling, an early response proinflammatory cytokine originated from monocytes and macrophages. 37 Besides the higher levels of IL-1 usually detected in hypertensive subjects, 37 the activation of the IL-1 receptor leads to sodium retention in the kidney through a mechanism that involves macrophages and nitric oxide production. 38 Moreover, fiber and acetate led to the downregulation of the transcription factor Egr1, considered a master regulator because it controls the expression of a wide range of genes and pathways implicated in CVD processes.…”

Sterile inflammation and pregnancy complications: a review

“…An important role of IL-1 as a contributor to hypertension has been proposed (Voelkel et al 1994, Zou et al 2001, Krishnan et al 2014. Additionally, IL-1 is known to exacerbate inflammation in placenta (Baergen et al 1994, Nadeau-Vallee et al 2015b, the key organ in PE.…”

Immune Mechanisms in Arterial Hypertension

“…Cellular damage increases extracellular ATP, which in turn serves as a danger signal that ultimately stimulates IL-1 release. 28 Interestingly, P237-deficient mice develop blunted hypertension in response to deoxycorticosterone acetate (DOCA) salt challenge, suggesting that the inflammasome is involved in the pathogenesis of hypertension. 29 Other stimuli for inflammasome activation include cholesterol and uric acid crystals.…”